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In their paper, Klaassen et al. present their findings on the revised Kids ITP Tools (KIT). This important work provides an update to the validated measure for evaluating health‐related quality of life (HRQoL) in children with immune thrombocytopenia (ITP). ITP, an acquired autoimmune disorder, results in thrombocytopenia and places children at risk for significant bleeding. Thankfully, the majority of children with ITP will have a brief disease course and no or mild bleeding symptoms. The rarity of severe bleeding events or the development of chronic disease provides a challenge with regard to clinical trial design, making alternative measures of pharmacological efficacy extremely important. Commentary on: Dhir et al. Quality of life in childhood immune thrombocytopenia: Revision of the Kids' ITP Tools (KIT). Br J Haematol 2024; 205:1489‐1496. [ABSTRACT FROM AUTHOR]

Chemoimmunotherapy followed by autologous stem cell transplantation ( ASCT) is a standard therapy for transplant-eligible patients with newly diagnosed mantle cell lymphoma ( MCL). The achievement of complete remission ( CR) and minimal residual disease ( MRD) negativity are associated with better outcomes. We tested an induction regimen of rituximab/bendamustine followed by rituximab/high-dose cytarabine ( RB/ RC). This phase 2 study ( NCT01661881) enrolled 23 transplant-eligible patients aged 42-69, of whom 70% were MCL international prognostic index low-risk. Patients received three cycles of RB followed by three cycles of RC. The primary endpoint of the trial was the rate of CR after six cycles of therapy, with a rate of 75% considered promising. 96% of patients achieved a CR/unconfirmed CR after treatment, meeting the primary objective. One patient progressed on study, one declined ASCT in CR, and the remaining 21 underwent successful stem cell collection and ASCT. After a median follow-up of 13 months, the progression-free survival rate was 96%. Among 15 MRD -evaluable patients who completed treatment, 93% achieved MRD negativity after RB/ RC. In conclusion, RB/ RC achieves very high CR and MRD negativity rates in transplant-eligible patients, with a favourable safety profile. RB/ RC warrants further comparative studies, and may become a useful alternative to RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-based induction regimens in this patient population. [ABSTRACT FROM AUTHOR]

Summary: Castleman disease (CD) describes a group of rare, potentially fatal lymphoproliferative disorders. To determine factors associated with mortality in CD, we analysed data from deceased patients in the ACCELERATE registry and compared them with matched controls. We analysed demographic, treatment and laboratory data from all deceased CD patients, matched controls and a subgroup of idiopathic multicentric Castleman disease (iMCD) patients. Of the 140 patients in ACCELERATE with a confirmed CD diagnosis, 10 had died. There were 72 patients with confirmed iMCD; six were deceased. The deceased CD cohort had more hospitalisations per year, higher overall hospitalisations and more days hospitalised per month, and received more treatment regimens per year than the matched‐control group. Analysis of laboratory values showed a significantly decreased absolute lymphocyte count at months 3 and 6 in the deceased cohort compared with controls. Among iMCD patients, there was a higher proportion of iMCD‐TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction and organomegaly) cases in the deceased group. The deceased iMCD group had significantly lower immunoglobulin M, international normalised ratio and platelet count. These data demonstrate that there may be differences between patients who have fatal and non‐fatal outcomes, and provide preliminary suggestions for parameters to evaluate further. [ABSTRACT FROM AUTHOR]

Summary: The inflammatory response to SARS/CoV‐2 (COVID‐19) infection may contribute to the risk of thromboembolic complications. α‐Defensins, antimicrobial peptides released from activated neutrophils, are anti‐fibrinolytic and prothrombotic in vitro and in mouse models. In this prospective study of 176 patients with COVID‐19 infection, we found that plasma levels of α‐defensins were elevated, tracked with disease progression/mortality or resolution and with plasma levels of interleukin‐6 (IL‐6) and D‐dimers. Immunohistochemistry revealed intense deposition of α‐defensins in lung vasculature and thrombi. IL‐6 stimulated the release of α‐defensins from neutrophils, thereby accelerating coagulation and inhibiting fibrinolysis in human blood, imitating the coagulation pattern in COVID‐19 patients. The procoagulant effect of IL‐6 was inhibited by colchicine, which blocks neutrophil degranulation. These studies describe a link between inflammation and the risk of thromboembolism, and they identify a potential new approach to mitigate this risk in patients with COVID‐19 and potentially in other inflammatory prothrombotic conditions. [ABSTRACT FROM AUTHOR]

Summary: SARS‐CoV‐2 infection can cause severe pneumonia (COVID‐19). There is evidence that patients with comorbidities are at higher risk of a severe disease course. The role of immunosuppression in the disease course is not clear. In the present report, we first describe two cases of persisting SARS‐CoV‐2 viraemia with fatal outcome in patients after rituximab therapy. [ABSTRACT FROM AUTHOR]

Summary: Chronic lymphocytic leukaemia (CLL) patients often have abnormal expansions of CD4+ and CD8+ T cells and this can be associated with progressive disease. To characterise the key T‐cell populations involved in this phenomenon, we used flow cytometry and 11 phenotypic markers to study 74 CLL patients and 14 controls. T cells of CLL patients were more phenotypically complex than those of healthy controls with significant increases in the frequencies of CD4 and CD8 memory T cells expressing exhaustion‐, activation‐ and senescence‐associated markers. Multivariate analysis of 111 different T‐cell subsets showed that high frequencies of four subsets (three CD8 and one CD4) were associated with shorter progression‐free survival. The most significant association was with CD4+HLA‐DR+PD‐1+ T cells, and patients could be stratified into high‐ and low‐risk groups based on the frequency of these T cells. The expansion of this CD4+ subset could not be accounted for by age, cytomegalovirus infection or increases in Treg cells. Overall, these results highlight two relatively simple biomarkers, percentage CD8+ and percentage CD4+PD‐1+HLA‐DR+ T cells, which can be used to risk‐stratify CLL patients, independent of other tumour‐associated markers. They also provide further evidence for the pivotal role of T cells in modulating the pathology of CLL. [ABSTRACT FROM AUTHOR]

Summary: Hypomethylating agents (HMAs) are standard of care for higher‐risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan‐histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single‐agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single‐agent HMAs. Forty‐five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma (MM) is a malignancy with varying survival outcomes and drivers of disease progression. Existing MM staging tools were developed using data from newly diagnosed patients. As patient characteristics and disease‐related factors change between diagnosis and the initiation of second‐line (2L) treatment, an unmet need exists for a tool that can evaluate risk of death at first relapse. We have developed a risk stratification algorithm (RSA) using data from patients with MM who were at 2L. Hazard ratios for independent predictors of overall survival (OS) were derived from a Cox models, and individual patient scores were calculated for total risk. K‐adaptive partitioning for survival was used to stratify patients into groups based on their scores. Relative risk doubled with ascending risk group; median OSs for patients in group 1 (lowest risk)–4 (highest risk) were 61·6, 29·6, 14·2 and 5·9 months, respectively. Differences in OS between risk groups were significant. Similar stratification was observed when the RSA was applied to an external validation data set. In conclusion, we have developed a validated RSA that can quantify total risk, frailty risk and disease aggressiveness risk, and stratify patients with MM at 2L into groups with profoundly different survival expectations. [ABSTRACT FROM AUTHOR]

The management of patients with immune thrombocytopenia ( ITP) is rapidly evolving. Over the last 15 years, a number of novel treatments have improved practice, with many steroid-sparing agents and a reduction in the progression to splenectomy. Although this has improved clinical care, many therapeutic challenges remain. There is no diagnostic test, no biomarkers to direct treatment and few comparative studies to help management decisions. Development of up to date guidelines is difficult with little high-grade evidence. First line treatment continues to be steroids and intravenous immunoglobulins ( IVIG) although both are often poorly tolerated and not curative. Common second line treatments include rituximab, immunosuppressive agents, such as azathioprine and mycophenolate mofetil, and the thrombopoietin receptor agonists romiplostim and eltrombopag. There are no comparative studies to decide between these agents and treatment is generally individualized, depending on comorbidity. Use of splenectomy has declined and is generally reserved for patients with chronic disease, although the exact position of splenectomy is subject to debate. Further understanding of the cause of disease in individual patients may help guide treatment. Randomized controlled studies of common treatments and novel treatments for refractory patients are urgently needed. [ABSTRACT FROM AUTHOR]

Advanced stage nodular lymphocyte predominant Hodgkin lymphoma ( nLPHL) is extremely rare in children and as a consequence, optimal treatment for this group of patients has not been established. Here we retrospectively evaluated the treatments and treatment outcomes of 41 of our patients from the UK and France with advanced stage nLPHL. Most patients received chemotherapy, some with the addition of the anti CD20 antibody rituximab or radiotherapy. Chemotherapy regimens were diverse and followed either classical Hodgkin lymphoma or B non-Hodgkin lymphoma protocols. All 41 patients achieved a complete remission with first line treatment and 40 patients are alive and well in remission. Eight patients subsequently relapsed and 1 patient died of secondary cancer (9 progression-free survival events). The median time to progression for those who progressed was 21 months (5·9-73·8). The median time since last diagnosis is 87·3 months (8·44-179·20). Thirty-six (90%), 30 (75%) and 27 (68%) patients have been in remission for more than 12, 24 and 36 months, respectively. Overall, the use of rituximab combined with multi-agent chemotherapy as first line treatment seems to be a reasonable therapeutic option. [ABSTRACT FROM AUTHOR]

With increasing number of therapies available for the treatment of multiple myeloma, it is timely to examine the course of patients' journeys. We investigated patient characteristics, treatment durations and outcomes, and symptom burden across the treatment pathway in Belgium, France, Germany, Italy, Spain, Switzerland and the UK. In total, 435 physicians retrospectively reviewed 4997 patient charts. Profiles of patients diagnosed with multiple myeloma during the last 12 months were similar across countries; bone pain was the most common presentation. Median duration of first-line therapy was 6 months, followed by a median treatment-free interval of 10 months; both these decreased with increasing lines of therapy, as did time to progression. Depth of response, as assessed by the treating physician, also decreased with each additional line of therapy: 74% of patients achieved at least a very good partial response at first line, compared with only 11% at fifth line. Deeper responses were associated with longer time to progression, although these were physician-judged. Toxicities and co-morbidities increased with later treatment lines, and were more likely to have led to discontinuation of treatment. These real-world data provide an insight into patient outcomes and treatment decisions being made in clinical practice. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 78-year-old patient who was treated for chronic myelomonocytic leukaemia (CMML) due to the development of circulating myeloblasts. The patient was diagnosed with isocitrate dehydrogenase (IDH) mutation following liquid chromatography-tandem mass spectrometry (LC/MS-MS)-based assay, polymerase chain reaction (PCR) amplification, and sequenom mass spectrometry. He developed progressive disease six months after taking mutant IDH2 inhibitor called AG-221.

Survival rates for elderly Hodgkin Lymphoma ( HL) have not improved substantially in recent years, mainly because of a lack of prospective randomized studies, due to difficulties in enrolling patients. Between 2002 and 2006, 54 untreated HL patients, aged between 65 and 80 years and considered 'non-frail' according to a comprehensive geriatric evaluation, were enrolled into a phase III randomized trial to compare a reduced-intensity regimen (vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone, bleomycin; VEPEMB) with standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Primary endpoint was progression-free survival ( PFS). Seventeen patients were in early stage (I- IIA), while 37 were advanced stage. Median age was 72 years and median follow-up was 76 months. Five-year PFS rates were 48% vs. 70% [adjusted Hazard ratio ( HR) = 2·19, 95% confidence interval ( CI) = 0·94-5·10, P = 0·068] and 5-year overall survival ( OS) rates were 63% vs. 77% (adjusted HR = 1·67, 95% CI = 0·69-4·03, P = 0·254) for VEPEMB compared to ABVD. Overall treatment-related mortality was 4%. World Health Organization grade 4 cardiac and lung toxicity occurred in four patients treated with ABVD versus no cases in the VEPEMB arm. Standard ABVD regimen resulted in better PFS and OS than the VEPEMB, although the differences were not statistically significant. The low toxicity of both treatments was probably attributable to stringent selection of patients based on a Comprehensive Geriatric Assessment that excluded frail patients. [ABSTRACT FROM AUTHOR]

The inherited macrothrombocytopenias constitute a subgroup of congenital platelet disorders that is the best characterized from the genetic point of view. This clinically heterogeneous subgroup is characterized by a variable degree of bleeding but without predisposition to haematological malignancies, as seen in the two other subgroups. The classification of inherited thrombocytopenia is traditionally based on the description of different clinical and biological features, in particular the measurement of the mean platelet volume. In certain disorders, biochemical platelet components are abnormal, and their analyses are useful in diagnosis. However, these approaches present several limitations, and many cases remain undiagnosed, especially for patients without a clear family history. An analysis of genetic abnormalities was subsequently used for classification, demonstrating that some different clinical entities were, in fact, identical. The genomic approach that was used initially to accurately link some phenotypic diagnoses with the causal genetic alteration was positional cloning and DNA sequencing. More recently, next generation sequencing in the form of whole-genome or -exome sequencing and RNA sequencing has been developed. This review will focus on the progress in understanding the different macrothrombocytopenias that have been identified. [ABSTRACT FROM AUTHOR]

The estimation of survival of myelodysplastic syndromes ( MDS) and risk of progression into acute myeloid leukaemia is challenging due to the heterogeneous clinical course. The most widely used prognostic scoring system (International Prognostic Scoring System [ IPSS]) was recently revised ( IPSS-R). The aim of this study was to investigate the prognostic relevance of flow cytometry ( FC) in the context of the IPSS-R. Bone marrow aspirates were analysed by FC in 159 patients with MDS. A flow score was calculated by applying the flow cytometric scoring system ( FCSS). Patients were assigned to IPSS and IPSS-R risk groups. The FCSS correlated with the World Health Organization classification, IPSS and IPSS-R risk groups. Mild flow cytometric abnormalities were associated with significantly better overall survival ( OS) and lower risk of disease evolution. The presence of aberrant myeloid progenitors was associated with transfusion dependency and disease progression. Most importantly, the FCSS identified prognostic subgroups within the IPSS-R cytogenetic good risk and low risk group. Flow cytometric analysis in patients with MDS provides additional prognostic information and is complementary to the IPSS-R. The addition of a flow cytometric score next to the clinical parameters within the IPSS-R is a further refinement of prognostication of patients with MDS. [ABSTRACT FROM AUTHOR]

Early recognition of children with chronic phase chronic myeloid leukaemia ( CML- CP) at risk for developing a lymphoid blast crisis (Ly BC) is desirable, because therapy options in CML- Ly BC are limited. We used Multiplex Ligation-dependent Probe Amplification to determine whether B-cell lymphoid leukaemia-specific copy number alterations ( CNAs) (e.g. IKZF1, PAX5, CDKN2A deletions) could be detected in CML- CP and may be used to predict disease progression to Ly BC. CNAs were detected in all patients with CML-Ly BC, but in none of the 77 patients with CML- CP. Based on this study we conclude that CNAs remain a hallmark of disease progression. [ABSTRACT FROM AUTHOR]

Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B- NHL), such as follicular lymphoma ( FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B- NHL and mantle cell lymphoma ( MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate ( ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival ( PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B- NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval ( CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted. [ABSTRACT FROM AUTHOR]

It is clear that cancers comprise a mixture of clones, a feature termed intra-clonal heterogeneity, that compete for spatial and nutritional resources in a fashion that leads to disease progression and therapy resistance. This process of competition resembles the schema proposed by Darwin to explain the origin of the species, and applying these evolutionary biology concepts to cancer has the potential to improve our treatment strategies. Multiple myeloma ( MM) has a unique set of characteristics that makes it a perfect model in which to study the presence of intra-clonal heterogeneity and its impact on therapy. Novel therapies have improved the outcome of MM patients, increasing both progression-free and overall survival. Current therapy comprises an induction, consolidation and maintenance phases and it is important to consider how these components of MM therapy are affected by the presence of intra-clonal heterogeneity. In this evolutionary context therapy can be considered as a selective pressure differentially acting on the myeloma clones and impacting on their chances of survival. In this review current knowledge of intra-clonal heterogeneity, as well as its impact on the different components of MM treatment is discussed. [ABSTRACT FROM AUTHOR]

The prognostic value of interim positron emission tomography ( PET) was evaluated after 2 cycles of doxorubicin, bleomycin, vinblastin and dacarbazine in classical Hodgkin lymphoma patients ( n = 229), based on Deauville criteria. In early stage non-bulky disease, bulky stage II disease, advanced stage low International Prognostic Score ( IPS ≤2) and advanced stage ( IPS ≥3), 3-year progression-free survival rates in PET2-negative vs. PET2-positive groups were 95·9% vs. 76·9% ( P < 0·0018), 83·3% vs. 20·0% ( P = 0·017), 77·0% vs. 30·0% ( P < 0·001) and 71·0% vs. 44·4%( P = 0·155), respectively. The outcome after positive PET2 was better than previously reported. The results from non-randomized studies of PET2-guided therapy would be valuable with careful interpretation. [ABSTRACT FROM AUTHOR]

Whole exome sequencing was performed in a patient with myelodysplastic syndrome before and after progression to acute myeloid leukaemia. Mutations in several genes, including SETBP1, were identified following leukaemic transformation. Screening of 328 patients with myeloid disorders revealed SETBP1 mutations in 14 patients (4·3%), 7 of whom had −7/del(7q) and 3 had i(17)(q10), cytogenetic markers associated with shortened overall survival and increased risk of leukaemic evolution. SETBP1 mutations were frequently acquired at the time of leukaemic evolution, coinciding with increase of leukaemic blasts. These data suggest that SETBP1 mutations may play a role in MDS and chronic myelomonocytic leukaemia disease progression. [ABSTRACT FROM AUTHOR]

Lenalidomide is an effective drug in low-risk myelodysplastic syndromes ( MDS) with isolated del(5q), although not all patients respond. Studies have suggested a role for TP53 mutations and karyotype complexity in disease progression and outcome. In order to assess the impact of complex karyotypes on treatment response and disease progression in 52 lenalidomide-treated patients with del(5q) MDS, conventional G-banding cytogenetics ( CC), single nucleotide polymorphism array ( SNP-A), and genomic sequencing methods were used. SNP-A analysis (with control sample, lymphocytes CD3+, in 30 cases) revealed 5q losses in all cases. Other recurrent abnormalities were infrequent and were not associated with lenalidomide responsiveness. Low karyotype complexity (by CC) and a high baseline platelet count (>280 × 109/l) were associated with the achievement of haematological response ( P = 0·020, P = 0·013 respectively). Unmutated TP53 status showed a tendency for haematological response ( P = 0·061). Complete cytogenetic response was not observed in any of the mutated TP53 cases. By multivariate analysis, the most important predictor for lenalidomide treatment failure was a platelet count <280 × 109/l (Odds Ratio = 6·17, P = 0·040). This study reveals the importance of a low baseline platelet count, karyotypic complexity and TP53 mutational status for response to lenalidomide treatment. It supports the molecular study of TP53 in MDS patients treated with lenalidomide. [ABSTRACT FROM AUTHOR]

Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma ( DLBCL) treated by three cycles of R- CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R- CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R- CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response ( PR). Five patients received additional local irradiation after PR at the end of the R- CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease ( PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R- CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R- CHOP alone. [ABSTRACT FROM AUTHOR]

The BCR- ABL1 transcript level at 3 months can predict long-term outcomes following frontline therapy with Imatinib or Dasatinib in chronic myeloid leukaemia ( CML) patients. However, data is lacking for second-generation tyrosine kinase inhibitor (2 GTKI) therapy after Imatinib failure. A total of 112 patients with CML in chronic phase receiving 2 GTKI after Imatinib failure were reviewed. Treatment outcomes including complete cytogenetic ( CCy R), major molecular ( MMR) and molecular response 4·5 (4·5 log reduction of BCR- ABL1 transcript level, MR4·5), treatment failure, progression-free and overall survival ( OS) were compared according to BCR- ABL1 transcript levels at 3 or 6 months, divided into <1% IS, 1-10% IS and ≥10% IS. BCR- ABL1 transcript level at 3 months showed better correlation with OS ( P < 0·001) than that at 6 months ( P = 0·147). Better OS was also observed in the patients achieving <1% IS (100%) and 1-10% IS (100%) than those with ≥10% IS at 3 months (70·6%, P < 0·001). Those with <1% IS showed the best CCyR, MMR and MR4·5 rates; 1-10% IS, intermediate; and ≥10% IS, the lowest CCyR, MMR and MR4·5 rates. The group with <1% IS at 3 months maintained significantly lower BCR- ABL1 transcript level compared to other two groups. In conclusion, the BCR- ABL1 transcript level at 3 months is the most relevant surrogate for outcomes following 2 GTKI therapy after Imatinib failure. [ABSTRACT FROM AUTHOR]

The prognosis of patients with relapsed and refractory acute leukaemia ( RRAL) is very poor. Forty patients with RRAL were enroled [28 acute myeloid leukaemia ( AML), 12 acute lymphoblastic leukaemia ( ALL)] in this Phase 1 dose-escalation trial of daily-infused clofarabine ( CLO) followed by cyclophosphamide ( CY) for four consecutive days ( CLO- CYx4). The median age was 48·5 years. The median number of prior regimens was 2 (range 1-5), and 6/40 patients (15%) had prior allogeneic haematopoietic stem cell transplant. 28/40 patients (70%) had adverse genetic features. 6/40 patients (15%) died within 60 d of induction (two infections, four progressive disease). The average time to neutrophil recovery (absolute neutrophil count ≥0·5 × 109/l was 34 d, (range, 17-78). The overall response rate ( ORR) was 33% (13/40), with seven complete remissions (18%), four complete remissions with incomplete recovery of blood counts (10%), and two partial remissions (5%). ORR was 25% (7/28), and 50% (6/12), for AML and ALL respectively. Notably, the clinical responses were independent of dose level. 7/17 patients (41%) exhibited CLO-mediated enhancement of CY-induced DNA, which was associated with, but not necessary for, improved clinical outcomes. In summary, the CLO- CYx4 regimen was well tolerated and had activity in patients with RRAL, especially relapsed ALL. Therefore, CLO- CYx4 can be considered a salvage therapy for adults with RRALs, and warrants further investigations. [ABSTRACT FROM AUTHOR]

Myelodysplastic/myeloproliferative uclassifiable ( MDS/ MPN- U) is a rare myeloid neoplasm characterized by myelodysplasia and myeloproliferation at the time of initial presentation, which is usually a diagnosis of exclusion. The molecular pathogenesis of MDS/ MPN- U patients remains to be elucidated. Among five patients diagnosed with MDS/ MPN- U, three patients harboured RUNX1 ( AML1) mutations; one carried somatic mosaicism of RUNX1 mutation with JAK2V617F mutation and one had dual RUNX1 and FLT3-internal tandem duplication mutations with progression to acute myeloid leukaemia ( AML). Germline mutation of TP53 was detected as a sole genetic lesion in one patient. JAK2V617F and somatic mosaicism of KRAS and TET2 mutations co-existed in one patient. Otherwise, no alterations were detected in PTPN11, NRAS, CBL and ASXL1 genes. ETV6- PDGFRB fusion transcript was not detected in all patients. Four patients recieved haematopoietic stem cell transplantation ( HSCT); three patients relapsed and one achieved complete remission after three donor lymphocyte infusions. Our findings suggest that the mutational spectrum observed in childhood MDS/ MPN- U is quite different from that seen in juvenile myelomonocytic leukaemia and, to some extent, resemble chronic myelomonocytic leukaemia. Moreover, two patients had constitutional alterations of genes frequently found in AML. Further investigations are required to define the roles of these genetic alterations in the pathogenesis of childhood MDS/ MPN- U. [ABSTRACT FROM AUTHOR]

Summary Epigenetic inactivation of tumour suppressor microRNAs has been implicated in carcinogenesis. We studied the promoter methylation of MIR203 in eight normal marrow controls, eight multiple myeloma (MM) cell lines, 20 monoclonal gammopathy of undetermined significance (MGUS), 123 diagnostic MM and 19 relapsed MM samples by methylation-specific polymerase chain reaction. Promoter of MIR203 was unmethylated in normal controls but homozygously methylated in 25% MM cell lines. Treatment with 5-Aza-2′-deoxycytidine led to promoter demethylation and MIR203 re-expression. Cyclic AMP responsive element binding protein 1 ( CREB1) mRNA was predicted as a MIR203 direct target. Luciferase activity was reduced in constructs carrying wild-type CREB1 3′UTR upon MIR203 expression but not in those carrying mutant CREB1 3′UTR. Moreover, restoration of MIR203 led to downregulation of CREB1 protein and inhibition of myeloma cell proliferation. In primary samples, MIR203 methylation occurred in 25·0% MGUS, 23·6% diagnostic MM, and 21·1% relapsed MM samples. In conclusion, MIR203 methylation is disease-specific with reversible gene silencing in MM. MIR203 is a tumour suppressor microRNA inhibiting cellular proliferation by targeting CREB1 mRNA in MM. Comparable occurrence of MIR203 methylation in MGUS and MM at diagnosis or relapse suggested that MIR203 methylation may be an early event in myelomagenesis instead of being acquired during disease progression. [ABSTRACT FROM AUTHOR]

The efficacy of allogeneic haematopoietic stem-cell transplantation (allo-HSCT) for natural killer (NK)-cell neoplasms is unknown. We investigated the results of allo-HSCT for NK-cell neoplasms between 1990 and 2003 through questionnaires. After reclassification by a haematopathologist, of 345 patients who underwent allo-HSCT for malignant lymphoma, 28 had NK-cell neoplasms (World Health Organization classification): extranodal NK/T-cell lymphoma ( n = 22), blastic NK-cell lymphoma ( n = 3), and aggressive NK-cell leukaemia ( n = 3). Twelve were chemosensitive and 16 chemorefractory. Twenty-two had matched-related donors. Stem-cell source was bone marrow in eight and mobilised peripheral blood in 20. Conditioning regimens were myeloablative ( n = 23) and non-myeloablative ( n = 5). Grade 2–4 acute graft- versus-host disease (GVHD) and chronic GVHD developed in 12 and 8 respectively. Eight died of disease progression, three of infection, two of acute GVHD, one of veno-occlusive disease, one of interstitial pneumonitis, and one of thrombotic microangiopathy. Two-year progression-free and overall survivals were 34% and 40% respectively (median follow-up, 34 months). All patients who did not relapse/progress within 10 months achieved progression-free survival (PFS) during the follow-up. In multivariate analysis, stem cell source (BM versus peripheral blood; relative risk 3·03), age (≥40 years vs. <40 years; relative risk 2·85), and diagnoses (extranodal NK/T-cell lymphoma versus others; relative risk 3·94) significantly affected PFS. Allo-HSCT is a promising treatment for NK-cell neoplasms. [ABSTRACT FROM AUTHOR]

The article discusses the study on the long-term survival after allogeneic stem cell transplantation (SCT) for advanced stage multiple myeloma. It states that 10 percent of myeloma patients experienced late progression and relapse after allo-SCT. It mentions that the use of novel drugs as part of conditioning and maintenance could prevent relapse.

The article focuses on a study carried out in 2012 at the department of Hematology of University Hospital of Tours in France regarding the vitamin C plasma level in patients followed for chronic lymphocytic leukaemia (CLL). It reports that the study highlights the issue of hypovitaminosis is in CLL patients but the reason for this deficiency remains unclear. Further it mentions that the study also raises a question regarding the role of vitamin C in the progression of the disease.

The article presents a study that determines the plasma levels of IL-33 among patients with multiple myeloma (MM). The study is conducted under the principles of the Declaration of Helsinki wherein patients were informed and written consent was derived from the patients. The study also uses the Durie-Salmon staging system and the utilization of immunoglopbulin G as paraprotein. The results of the study show that the deficiency in cytokine secretion worsens during disease progression.